ABSTRACT Atherosclerosis is a chronic inflammatory disease accompanied by local production and release of cytokines such as interferon gamma (IFNg), which is produced by T-cells in lesions. Atherogenic effects of IFNg are well supported in murine studies. Exogenous administration of IFNg enhanced lesion formation while knockout of IFNg or its receptor reduced lesion size. Although IFNg plays an important role in atherogenesis, the mechanism(s) by which it promotes disease progression and the dietary conditions that support its induction are incompletely understood. Moreover, attempts to antagonize IFNg for the treatment of atherosclerosis have not been maximized because IFNg is also essential for host defense. In preliminary work, we show that low, ?metabolic disease-appropriate? doses of IFNg are sufficient to target a pro-atherogenic macrophage protein network (MSRN), but insufficient to induce the canonical IFNg signaling required for host defense functions. We further show that knocking out or attenuating components of this canonical IFNg signaling block IFNg-mediated host defense functions, but do not block IFNg action on the MSRN. Finally, we provide evidence that obesity/insulin resistance is both necessary and sufficient to induce IFNg production by splenic T-cells, target macrophage MSRN proteins, and promote macrophage cholesterol accumulation. These latter findings raise the possibility that this macrophage IFNg-MSRN pathway might help to explain why patients with type 2 diabetes are so highly predisposed to developing atherosclerosis. Based on these findings, this proposal seeks to test two interrelated hypotheses. First, we will test the hypothesis that IFNg targets MSRN proteins and promotes atherogenesis through a mechanism that is independent of its function in host defense. Second, we will test the hypothesis that this macrophage IFNg- MSRN pathway is selective to obesity and insulin resistance-accelerated atherogenesis. To achieve these goals, we propose three aims: (1) identify mechanism(s) by which IFNg targets MSRN proteins and increases cholesterol accumulation in macrophages, (2) determine the contribution of macrophage IFNg signaling to atherosclerosis in the presence and absence of obesity and insulin resistance in mice, and (3) determine the effect of type 2 diabetes on MSRN proteins in human artery wall macrophages. By integrating mechanistic animal and cellular studies with human observation, our proposed work seeks to define clinically relevant pathways by which the induction of IFNg during type 2 diabetes promotes atherogenesis through host defense-independent pathways. Elucidating pathways that differentiate between the pro-atherogenic and host defense properties of IFNg is important to develop new approaches to therapeutically target IFNg biology in patients with cardiovascular disease without predisposing them to opportunistic infections.